Diagnostic probability classification in suspected borreliosis by a novel Borrelia C6-peptide IgG1- subclass antibody test

The tick-borne multisystemic infection caused by Borrelia burgdorferi sensu lato, Lyme borreliosis, or Lyme disease, occurring in temperate regions of the northern hemisphere, continues to spread geographically with the expanding tick population. Despite the rising perceived risk of infection in the population, the clinical diagnosis of Borrelia infection is not always obvious and the most important laboratory test, antibody detection, has limited accuracy in diagnosing active disease. According to international guidelines, the primary serology test, which has a high sensitivity-low specificity, should, be verified using a high specificity confirmation test to improve the specificity. However, this enhancement in specificity comes at the cost of lower sensitivity. This two-step procedure is often omitted in everyday clinical practice. An optimal primary test would be one where no secondary tests for confirmation would be necessary. In the present study, the performance of a novel assay for quantitating IgG1-subclass antibodies to Borrelia C6-peptide was compared to a commercial reference assay of total IgG and IgM antibodies to Borrelia C6-peptide in the setting of a high endemic area for borreliosis. A derivation study on a retrospective clinical material was performed to compare the performance parameters and assess the discriminatory properties of the assays, followed by a prospective validation study. The IgG1-antibody assay achieved comparable summary performance parameters to those of the reference assay. The sensitivity was almost 100% while the specificity was about 50%. In a high-endemic setting, characterized by high background seropositivity of about 50% and disease prevalence of approximately 10%, antibody tests are unable to rule-in active Borrelia infection. The rule-out assessment of the methods revealed that of 1000 patients, 7 – 54 with negative results based on the reference method could have an active Borrelia infection. Such uncertainty was not found for the index test and may help improve the risk classification of patients

EU-päätöslauselma hämmentää Lymen borrelioosin hoitoa

Euroopan parlamentti on ottanut infektiolääkäreitä kuulematta kantaa Lymen borrelioosin diagnostiikkaan ja hoitoon. Päätös¬lauselma on monilta osin epätieteellinen ja voi johtaa potilaiden hoidossa väärille ja vaarallisillekin linjoille

Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM—a prospective, randomized, single-centre, open-label study

ObjectivesSevere COVID-19 is associated with an imbalanced immune response. We hypothesized that patients with enhanced inflammation, as demonstrated by increased levels of certain inflammatory biomarkers, would benefit from interleukin-6 blockage.MethodsPatients hospitalized with COVID-19, hypoxemia, and at least two of four markedly elevated markers of inflammation (interleukin-6, C-reactive protein, ferritin, and/or D-dimer) were randomized for tocilizumab (TCZ) plus standard of care (SoC) or SoC alone. The primary endpoint was clinical status at day 28 assessed using a seven-category ordinal scale, and the secondary endpoints included intensive care unit admission, respiratory support, and duration of hospital admission.ResultsClinical status at day 28 was significantly better in patients who received TCZ in addition to SoC compared with those who received SoC alone (p = 0.037). By then, 93% of patients who received TCZ (n = 53 of 57) and 86% of control patients (n = 25 of 29) had been discharged from the hospital. In addition, 47% of TCZ patients (n = 27 of 57) and 24% of control patients (n = 7 of 29) had resumed normal daily activities. The median length of hospitalization was 9 days (interquartile range, 7–12) in the TCZ group and 12 days (interquartile range, 9–15) in the control group (p = 0.014).DiscussionIn patients hospitalized with COVID-19, hypoxemia, and elevated inflammation markers, administration of TCZ in addition to SoC was associated with significantly better clinical recovery by day 28 and a shorter hospitalization compared with SoC alone.</p

Relation between dietary cadmium intake and biomarkers of cadmium exposure in premenopausal women accounting for body iron stores

<p>Abstract</p> <p>Background</p> <p>Cadmium is a widespread environmental pollutant with adverse effects on kidneys and bone, but with insufficiently elucidated public health consequences such as risk of end-stage renal diseases, fractures and cancer. Urinary cadmium is considered a valid biomarker of lifetime kidney accumulation from overall cadmium exposure and thus used in the assessment of cadmium-induced health effects. We aimed to assess the relationship between dietary cadmium intake assessed by analyses of duplicate food portions and cadmium concentrations in urine and blood, taking the toxicokinetics of cadmium into consideration.</p> <p>Methods</p> <p>In a sample of 57 non-smoking Swedish women aged 20-50 years, we assessed Pearson's correlation coefficients between: 1) Dietary intake of cadmium assessed by analyses of cadmium in duplicate food portions collected during four consecutive days and cadmium concentrations in urine, 2) Partial correlations between the duplicate food portions and urinary and blood cadmium concentrations, respectively, and 3) Model-predicted urinary cadmium concentration predicted from the dietary intake using a one-compartment toxicokinetic model (with individual data on age, weight and gastrointestinal cadmium absorption) and urinary cadmium concentration.</p> <p>Results</p> <p>The mean concentration of cadmium in urine was 0.18 (+/- s.d.0.12) μg/g creatinine and the model-predicted urinary cadmium concentration was 0.19 (+/- s.d.0.15) μg/g creatinine. The partial Pearson correlations between analyzed dietary cadmium intake and urinary cadmium or blood concentrations were r = 0.43 and 0.42, respectively. The correlation between diet and urinary cadmium increased to r = 0.54 when using a one-compartment model with individual gastrointestinal cadmium absorption coefficients based on the women's iron status.</p> <p>Conclusions</p> <p>Our results indicate that measured dietary cadmium intake can reasonably well predict biomarkers of both long-term kidney accumulation (urine) and short-term exposure (blood). The predictions are improved when taking data on the iron status into account.</p

Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans

Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.Original Publication: Johanna Sjöwall, Linda Fryland, Marika Nordberg, Florence Sjögren, Ulf Garpmo, Christian Jansson, Sten-Anders Carlsson, Sven Bergstrom, Jan Ernerudh, Dag Nyman, Pia Forsberg and Christina Ekerfelt, Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans, 2011, PLOS ONE, (6), 3, 0018220. http://dx.doi.org/10.1371/journal.pone.0018220 Copyright: Public Library of Science (PLoS) http://www.plos.org

Tick-Borne Infections in Humans : Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum

The tick-borne infectious agents, B. burgdorferi, A. phagocytophilum and the TBE-virus, can all cause clinical disease in humans and may all initially give rise to myalgia, arthralgia, headache and fever. The clinical manifestations of the infections range from subclinical or mild to severe, in some cases with a postinfectious sequel, and mixed infections may occur, confusing the clinical picture. The aim of this thesis was to investigate the occurrence and co-existence of these infections in a Scandinavian context. A further aim was to study aspects of the immunopathogenesis of B. burgdorferi infection and possible effects on the immune response when previously exposed to A. phagocytophilum. Finally, an attempt was made to improve the laboratory diagnosis of Lyme neuroborreliosis (LNB). In a prospective clinical study, patients were recruited based on two independent inclusion criteria; 1) patients with unspecific symptoms or fever, and 2) patients with erythema migrans (EM). Among 206 patients, we found 186 cases of Lyme borreliosis (LB) (174 with EM), 18 confirmed and two probable cases of human granulocytic anaplasmosis (HGA), and two cases of Tick-borne encephalitis (TBE). Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a subclinical co-infection with A. phagocytophilum, based on serology. Both TBE cases had co-infections, one with B. burgdorferi and one with A. phagocytophilum. In another investigation, IL-12p70 secretion in patients with current LB was compared in patients with or without previous A. phagocytophilum infection. Patients with serological evidence of previous exposure to A. phagocytophilum had a lower B. burgdorferi-induced IL-12p70 secretion. Since IL-12p70 induces the Th1 response, this finding indicates a reduced Th1 response, possibly caused by A. phagocytophilum. In a separate study, we showed that patients with LNB had increased levels of cytokines associated with cytotoxicity in cerebrospinal fluid (CSF), including the recently described cytokine IL-17. Since it is known that the adaptive immune system, especially the T cells, is activated during an infection with B. burgdorferi, a modified ELISPOT assay using cells from CSF was evaluated to be a useful complementary test in diagnosing LNB. However, we found that the diagnostic performance was too weak in our setting, and we could not recommend it for use in clinical laboratories at this stage. In conclusion, tick-borne co-infections are probably quite common in Sweden. Our HGA cases were most often discovered as co-infections with LB and would probably have been missed during a routine consultation. They presented with mild symptoms and often without fever, which in previous reports has been part of the disease definition. The immune response in LNB was shown to be compartmentalized to the target organ, also in terms of cytokine response. Furthermore, we found indications of possible long-term effects of A. phagocytophilum infection, demonstrated as a reduced IL-12p70 secretion in patients with ongoing LB. This could be a disadvantage when mounting a Th1 response to infection with B. burgdorferi. If this is so, the inter-play of these infectious agents in co-infections or consecutive infections may be of importance to clinical outcome

Tick-Borne Infections in Humans : Aspects of immunopathogenesis, diagnosis and co-infections with Borrelia burgdorferi and Anaplasma phagocytophilum

The tick-borne infectious agents, B. burgdorferi, A. phagocytophilum and the TBE-virus, can all cause clinical disease in humans and may all initially give rise to myalgia, arthralgia, headache and fever. The clinical manifestations of the infections range from subclinical or mild to severe, in some cases with a postinfectious sequel, and mixed infections may occur, confusing the clinical picture. The aim of this thesis was to investigate the occurrence and co-existence of these infections in a Scandinavian context. A further aim was to study aspects of the immunopathogenesis of B. burgdorferi infection and possible effects on the immune response when previously exposed to A. phagocytophilum. Finally, an attempt was made to improve the laboratory diagnosis of Lyme neuroborreliosis (LNB). In a prospective clinical study, patients were recruited based on two independent inclusion criteria; 1) patients with unspecific symptoms or fever, and 2) patients with erythema migrans (EM). Among 206 patients, we found 186 cases of Lyme borreliosis (LB) (174 with EM), 18 confirmed and two probable cases of human granulocytic anaplasmosis (HGA), and two cases of Tick-borne encephalitis (TBE). Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a subclinical co-infection with A. phagocytophilum, based on serology. Both TBE cases had co-infections, one with B. burgdorferi and one with A. phagocytophilum. In another investigation, IL-12p70 secretion in patients with current LB was compared in patients with or without previous A. phagocytophilum infection. Patients with serological evidence of previous exposure to A. phagocytophilum had a lower B. burgdorferi-induced IL-12p70 secretion. Since IL-12p70 induces the Th1 response, this finding indicates a reduced Th1 response, possibly caused by A. phagocytophilum. In a separate study, we showed that patients with LNB had increased levels of cytokines associated with cytotoxicity in cerebrospinal fluid (CSF), including the recently described cytokine IL-17. Since it is known that the adaptive immune system, especially the T cells, is activated during an infection with B. burgdorferi, a modified ELISPOT assay using cells from CSF was evaluated to be a useful complementary test in diagnosing LNB. However, we found that the diagnostic performance was too weak in our setting, and we could not recommend it for use in clinical laboratories at this stage. In conclusion, tick-borne co-infections are probably quite common in Sweden. Our HGA cases were most often discovered as co-infections with LB and would probably have been missed during a routine consultation. They presented with mild symptoms and often without fever, which in previous reports has been part of the disease definition. The immune response in LNB was shown to be compartmentalized to the target organ, also in terms of cytokine response. Furthermore, we found indications of possible long-term effects of A. phagocytophilum infection, demonstrated as a reduced IL-12p70 secretion in patients with ongoing LB. This could be a disadvantage when mounting a Th1 response to infection with B. burgdorferi. If this is so, the inter-play of these infectious agents in co-infections or consecutive infections may be of importance to clinical outcome

Morgondagens skärgårdskvinnor

Under en längre tid har en negativ befolkningstrend pågått i skärgården. Det blir allt svårare att bo på öar utan fast vägförbindelse och statistiken visar att det främst är kvinnor som flyttar bort. För att kunna hålla skärgården levande måste inflyttningen öka och könsfördelningen behöver bli jämnare. Det här är ett arbete inom projektet ”Morgondagens skärgårdskvinnor”. Syftet med arbetet är tvådimensionellt. Dels är syftet att utreda in- och utflyttningsorsaker bland kvinnor och dels att bidra med kunskap som kan användas för att utveckla fortsatt datainsamling inom projektet hösten 2017. Målgruppen har begränsats till kvinnor i åldern 20 till 65 som bor på eller flyttat från en ö utan fast vägförbindelse i Åbolands, Ålands och Stockholms skärgård. Arbetet baseras på en litteraturgenomgång, i vilken det har tagits upp viktiga villkor för livet i skärgården. Datainsamlingen har gjorts både ur ett kvantitativt och kvalitativt perspektiv genom en pilotenkät, fokusgruppintervjuer och individuella intervjuer. Sammanlagt har 160 kvinnor deltagit i undersökningarna. I resultaten kan ses att miljön och de sociala relationerna är viktiga vid valet av boningsort. Likväl bör trafikförbindelserna, serviceutbudet och social- och hälsovårdstjänsterna utvecklas och förbättras. För att skapa förutsättningar för ett aktivt liv i skärgården behövs förändring och nytänk.Saaristossa on tapahtunut negatiivinen väestömuutos pidemmällä ajanjaksolla. On yhä vaikeampaa asua saarilla ilman kiinteää tieyhteyttä ja tilastoiden mukaan naiset ennen kaikkea ovat he, jotka muuttavat pois. Jotta voitaisiin pitää saaristo elävänä, on muuttaminen saaristosta saatava kääntymään muuttamiseksi saaristoon sekä saada sukupuolten välinen jakauma tasapainoon. Tämä työ kuuluu projektiin ”Huomispäivän saaristolaisnaiset”. Työn tarkoitus on kaksiulotteinen. Osittain on tavoitteena ollut selvittää syitä naisten muuttoon saaristoon ja saaristosta pois sekä osittain tuoda tietoa, jota voitaisiin käyttää hyväksi kehiteltäessä tiedonkeruuta projektin jatkuessa syksyllä 2017. Kohderyhmä on rajattu 20-vuotiaista 65- vuotiaisiin naisiin, jotka asuvat Turunmaan, Ahvenanmaan ja Tukholman saaristoissa ilman kiinteää tieyhteyttä tai ovat muuttaneet pois mainituilta alueilta. Työ perustuu kirjallisuuskatsaukseen, jossa tarkastellaan tärkeitä elämisen edellytyksiä saaristossa. Tiedonkeruu pohjautuu sekä määrälliseen näkökulmaan pilottikyselylomakkeella että laadulliseen näkökulmaan kohderyhmä- että yksilöhaastatteluissa. Tutkimuksiin osallistui kaiken kaikkeaan 160 naista. Tuloksesta selviää, että ympäristö ja sosiaaliset suhteet ovat tärkeitä asuinpaikan valinnassa. Liikenneyhteyksiä, palvelutarjontaa sekä sosiaali- ja terveydenhoitopalveluja on kehitettävä ja parannettava. Jotta voitaisiin saada aikaan edellytykset aktiiviseen elämään saaristossa, tarvitaan muutoksia ja uusajattelua.The Finnish archipelago has endured a reduction of its population during a longer period of time. It is exceedingly difficult to live on islands without permanent road links to the mainland and statistics show that it is mainly women who move away from these islands and settle elsewhere. Improvement in immigration and a better gender balance amongst the population is necessary to keep the archipelago alive. This is a thesis of the project “The Archipelagic Women of Tomorrow”. The purpose of the assignment is two-dimensional. A part of the study is to investigate the reasons behind immigration and emigration amongst women in the archipelago, while another part is to contribute with knowledge for developing the collecting of data in the project during the autumn of 2017. The target group is limited to women between 20-65 years of age that live on or have moved away from an island without permanent road links to the mainland in the archipelago of Turku, Åland or Stockholm. The purpose of the study is to give the project a solid basis on which to build future studies on. The thesis is built on a review of literature that brings attention to crucial terms and conditions of life in the archipelago. The collecting of data has been done from a quantitative and qualitative perspective through a pilot survey, group interviews as well as individual ones. A total of 160 women have taken part in the study and made their voices heard in the interviews or questionnaire. The results show that the environment and social relations helps tip the scale when the women have been faced with the decision on where to live. Other important issues such as traffic connections between mainland and islands, the range of services and the development of social- and health care services were brought to the surface as important factors in the decision making. A change and new ways of thinking are prerequisites for active life in the archipelago

Linköping University Medical Dissertations No. 1315 Tick-Borne Infections in Humans

Aspects of immunopathogenesis, diagnosis and co-infections wit

Aetiology of Tick-Borne Infections in an Adult Swedish Population - Are Co-Infections with Multiple Agents Common?

In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (≥38.0˚C) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM), following an observed tick bite or tick exposure within one month prior to onset of symptoms. A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical co-infection with Anaplasma phagocytophilum, based on serology. Both TBE cases had co-infections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors